There are large individual differences in drug abuse vulnerabilities among humans that are likely to display genetic as well as environmental components. During this FY, these investigators continued to explore possible roles of allelic variants at candidate gene loci in possibly contributing to human individual differences in drug abuse vulnerability, and to establish groundwork for genome scanning approaches to identifying previously-unanticipated genes conferring drug abuse vulnerabilities. This work revealed patterns of linkage disequilibrium at the dopamine transporter and D2 dopamine receptor gene loci and with flanking gene markers that allows improved interpretation of initially-positive association findings in substance abuse, the paranoia associated with cocaine use, and in attention deficit/hyperactivity disorder, which is a significant drug-abuse comorbidity. It sharpened attention to features of a previously-reported association between novelty-seking and DRD4 polymorphisms. It identified a COMT functional variant highly associated with substance abuse vulnerability. It revealed no asociation with candidate markers at the DRD3 locus. These workers aided studies of the diagnostic criteria for drug abuse that appear to display substantial genetic and those that display substantial environmental influences, and established affected-sib pair strategies that would allow approaches to positional identification of alleles that enhance drug abuse vulnerability in man.